Bariatric Surgery Induces Alterations in the Immune Profile of Peripheral Blood T Cells.

Low-grade inflammation is closely linked to obesity and obesity-related comorbidities; therefore, immune cells have become an important topic in obesity research. Here, we performed a deep phenotypic characterization of circulating T cells in people with obesity, using flow cytometry. Forty-one individuals with obesity (OB) and clinical criteria for bariatric surgery were enrolled in this study. We identified and quantified 44 different circulating T cell subsets and assessed their activation status and the expression of immune-checkpoint molecules, immediately before (T1) and 7-18 months after (T2) the bariatric surgery. Twelve age- and sex-matched healthy individuals (nOB) were also recruited. The OB participants showed higher leukocyte counts and a higher percentage of neutrophils. The percentage of circulating Th1 cells were negatively correlated to HbA1c and insulin levels. OB Th1 cells displayed a higher activation status and lower PD-1 expression. The percentage of Th17 and Th1/17 cells were increased in OB, whereas the CD4+ Tregs' percentage was decreased. Interestingly, a higher proportion of OB CD4+ Tregs were polarized toward Th1- and Th1/17-like cells and expressed higher levels of CCR5. Bariatric surgery induced the recovery of CD4+ Treg cell levels and the expansion and activation of Tfh and B cells. Our results show alterations in the distribution and phenotype of circulating T cells from OB people, including activation markers and immune-checkpoint proteins, demonstrating that different metabolic profiles are associated to distinct immune profiles, and both are modulated by bariatric surgery.

Role of CD20+ T cells in cancer, autoimmunity and obesity.

Despite the known link between obesity and insulin resistance (IR) to chronic low-grade inflammation, new markers capable of early IR detection are needed. Immune cells are components of adipose tissue's (AT) stromal vascular fraction (SVF) that regulate AT homeostasis. The altered phenotype and function of AT-infiltrating immune cells may contribute to the development and maintenance of local AT inflammation observed under obesity-induced IR conditions. Impaired AT-specific immunometabolic function may influence the whole organism. Therefore, AT-infiltrating immune cells may be important players in the development of obesity-related metabolic complications, such as type 2 diabetes mellitus (T2DM). B and T cells, particularly CD20+ T cells, play important roles in human pathology, such as autoimmune disease and cancer. However, the question remains as to whether CD20+ T cells have an important contribution to the development of obesity-related IR. While circulating CD20+ T cells are mostly of the central memory phenotype (i.e. antigen-experienced T cells with the ability to home to secondary lymphoid organs), tissues-infiltrated CD20+ T cells are predominantly of the effector memory phenotype (i.e. antigen-experienced T cells that preferentially infiltrate peripheral tissues). The latter produce pro-inflammatory cytokines, such as IFN-γ and IL-17, which play a role in obesity-related IR development. This review describes the CD20 molecule and its presence in both B and T cells, shedding light on its ontogeny and function, in health and disease, with emphasis on AT. The link between CD20+ T cell dysregulation, obesity, and IR development supports the role of CD20+ T cells as markers of adipose tissue dysmetabolism.

Real-time OXPHOS capacity analysis in wounded skin from diabetic mice: A pilot study.

INTRODUCTION: Diabetes mellitus (DM) impairs wound healing. The aim was to determine whether DM influences mitochondrial respiration in wounded skin (WS) and non-wounded skin (NWS), in a pre-clinical wound healing model of streptozotocin (STZ)-induced diabetes. METHODS: Six weeks after diabetes induction, two wounds were created in the back of C57BL/J6 mice. Using high-resolution respirometry (HRR), oxygen flux was measured, in WS and NWS, using two substrate-uncoupler-inhibitor titration protocols, at baseline (day 0), day 3 and 10 post-wounding, in STZ-DM and non-diabetic (NDM) mice. Flux control ratios for the oxidative phosphorylation (OXPHOS) capacity were calculated. RESULTS: A significant increase in mitochondrial respiration was observed in STZ-DM skin compared to control skin at baseline. The OXPHOS capacity was decreased in WS under diabetes at day 3 post-wounding (inflammation phase). However, at day 10 post-wounding (remodeling phase), the OXPHOS capacity was higher in WS from STZ-DM compared to NDM mice, and compared to NWS from STZ-DM mice. A significant relative contribution of pyruvate, malate and glutamate (PMG) oxidation to the OXPHOS capacity was observed in WS compared to NWS from STZ-DM mice, at day 10, while the relative contribution of fatty acid oxidation to the OXPHOS capacity was higher in NWS. The OXPHOS capacity is altered in WS from STZ-DM compared to NDM mice across the healing process, and so is the substrate contribution in WS and NWS from STZ-DM mice, at each time point. CONCLUSION: HRR may be a sensitive tool to evaluate the underlying mechanisms of tissue repair during wound healing.

CD8+ Treg cells play a role in the obesity-associated insulin resistance.

Obesity-related chronic low-grade inflammation may trigger insulin resistance and type 2 diabetes (T2D) development. Cells with regulatory phenotype have been shown to be reduced during obesity, especially CD4+ Treg cells. However, little is known about the CD8+ Treg cells. Therefore, we aim to characterize the CD8+ Treg cells in human peripheral blood and adipose tissue, specifically, to address the effect of obesity and insulin resistance in this regulatory immune cell population. A group of 42 participants with obesity (OB group) were recruited. Fourteen of them were evaluated pre- and post-bariatric surgery. A group of age- and sex-matched healthy volunteers (n = 12) was also recruited (nOB group). CD8+ Treg cell quantification and phenotype were evaluated by flow cytometry, in peripheral blood (PB), subcutaneous (SAT), and visceral adipose tissues (VAT). The OB group displayed a higher percentage of CD8+ Treg cells in PB, compared to the nOB. In addition, they were preferentially polarized into Tc1- and Tc1/17-like CD8+ Treg cells, compared to nOB. Moreover, SAT displayed the highest content of CD8+ Tregs infiltrated, compared to PB or VAT, while CD8+ Tregs infiltrating VAT displayed a higher percentage of cells with Tc1-like phenotype. Participants with pre-diabetes displayed a reduced percentage of TIM-3+CD8+ Tregs in circulation, and PD-1+CD8+ Tregs infiltrated in the VAT. An increase in the percentage of circulating Tc1-like CD8+ Treg cells expressing PD-1 was observed post-surgery. In conclusion, obesity induces significant alterations in CD8+ Treg cells, affecting their percentage and phenotype, as well as the expression of important immune regulatory molecules.

Healing profiles in patients with a chronic diabetic foot ulcer: An exploratory study with machine learning.

Diabetic foot ulcers (DFU) are one of the most frequent and debilitating complications of diabetes. DFU wound healing is a highly complex process, resulting in significant medical, economic and social challenges. Therefore, early identification of patients with a high-risk profile would be important to adequate treatment and more successful health outcomes. This study explores risk assessment profiles for DFU healing and healing prognosis, using machine learning predictive approaches and decision tree algorithms. Patients were evaluated at baseline (T0; N = 158) and 2 months later (T1; N = 108) on sociodemographic, clinical, biochemical and psychological variables. The performance evaluation of the models comprised F1-score, accuracy, precision and recall. Only profiles with F1-score >0.7 were selected for analysis. According to the two profiles generated for DFU healing, the most important predictive factors were illness representations on T1 IPQ-B (IPQ-B ≤ 9.5 and < 10.5) and the DFU duration (≤ 13 weeks). The two predictive models for DFU healing prognosis suggest that biochemical factors are the best predictors of a favorable healing prognosis, namely IL-6, microRNA-146a-5p and PECAM-1 at T0 and angiopoietin-2 at T1. Illness perception at T0 (IPQ-B ≤ 39.5) also emerged as a relevant predictor for healing prognosis. The results emphasize the importance of DFU duration, illness perception and biochemical markers as predictors of  healing in chronic DFUs. Future research is needed to confirm and test the obtained predictive models.

Impact of Psychological Distress on Physiological Indicators of Healing Prognosis in Patients with Chronic Diabetic Foot Ulcers: A Longitudinal Study.

Objective: Diabetic foot ulcers (DFUs) are devastating complications of diabetes, responsible for a high number of amputations worldwide. Due to its impact on chronic inflammation, psychological distress may negatively impact the healing process. Thus, this study evaluated the influence of psychological distress on physiological indicators of healing prognosis and the potential of stress-reducing therapies for DFU healing. Approach: Patients with chronic DFU were recruited and assessed at enrollment and 2 months later. According to psychological scores at enrollment, participants were allocated into groups without (group 1) or with (group 3) psychological distress. Participants who reported clinical distress were then randomly allocated into a control (no stress-reducing intervention-group 4) or experimental (with stress-reducing interventions-group 5) group. Subsequently, indicators of healing prognosis were measured. Results: Groups 1 and 3 presented no differences in the Perfusion, Extent, Depth, Infection and Sensation score, glycated hemoglobin, or inflammatory and angiogenic markers. However, the immune cell ratio was increased by more than twofold in group 3, compared with group 1. Importantly, the expression of circulating microRNAs was significantly increased in group 3 (miR-21-5p, miR-155-5p, miR-146a-5p, and miR-221-3p [p < 0.05]), compared with group 1. Two months later, group 5 displayed a significant improvement in the Perceived Stress Scale and Hospital Anxiety and Depression Scale scores (p < 0.01), and the immune cell ratio was decreased by more than 2.5-fold. Innovation: This study helped to identify which variables and psychological interventions are more successful in promoting DFU healing. Conclusion: Psychological distress influenced clinical and physiological parameters, leading to compromised DFU healing and consequently underlining the potential of adjuvant stress-reducing approaches.

Innovative Functional Biomaterials as Therapeutic Wound Dressings for Chronic Diabetic Foot Ulcers.

The imbalance of local and systemic factors in individuals with diabetes mellitus (DM) delays, or even interrupts, the highly complex and dynamic process of wound healing, leading to diabetic foot ulceration (DFU) in 15 to 25% of cases. DFU is the leading cause of non-traumatic amputations worldwide, posing a huge threat to the well-being of individuals with DM and the healthcare system. Moreover, despite all the latest efforts, the efficient management of DFUs still remains a clinical challenge, with limited success rates in treating severe infections. Biomaterial-based wound dressings have emerged as a therapeutic strategy with rising potential to handle the tricky macro and micro wound environments of individuals with DM. Indeed, biomaterials have long been related to unique versatility, biocompatibility, biodegradability, hydrophilicity, and wound healing properties, features that make them ideal candidates for therapeutic applications. Furthermore, biomaterials may be used as a local depot of biomolecules with anti-inflammatory, pro-angiogenic, and antimicrobial properties, further promoting adequate wound healing. Accordingly, this review aims to unravel the multiple functional properties of biomaterials as promising wound dressings for chronic wound healing, and to examine how these are currently being evaluated in research and clinical settings as cutting-edge wound dressings for DFU management.

Are gut dysbiosis, barrier disruption, and endotoxemia related to adipose tissue dysfunction in metabolic disorders? Overview of the mechanisms involved.

Recently, compelling evidence points to dysbiosis and disruption of the epithelial intestinal barrier as major players in the pathophysiology of metabolic disorders, such as obesity. Upon the intestinal barrier disruption, components from bacterial metabolism and bacteria itself can reach peripheral tissues through circulation. This has been associated with the low-grade inflammation that characterizes obesity and other metabolic diseases. While circulating bacterial DNA has been postulated as a common feature of obesity and even type 2 diabetes, almost no focus has been given to the existence and effects of bacteria in peripheral tissues, namely the adipose tissue. As a symbiont population, it is expected that gut microbiota modulate the immunometabolism of the host, thus influencing energy balance mechanisms and inflammation. Gut inflammatory signals cause direct deleterious inflammatory responses in adipose tissue and may also affect key gut neuroendocrine mechanisms governing nutrient sensing and energy balance, like incretins and ghrelin, which play a role in the gut-brain-adipose tissue axis. Thus, it is of major importance to disclose how gut microbiota and derived signals modulate neuroendocrine and inflammatory pathways, which contribute to the dysfunction of adipose tissue and to the metabolic sequelae of obesity and related disorders. This review summarizes the current knowledge regarding these topics and identifies new perspectives in this field of research, highlighting new pathways toward the reduction of the inflammatory burden of metabolic diseases.

Green Antimicrobials as Therapeutic Agents for Diabetic Foot Ulcers.

Diabetic foot ulcers (DFU) are one of the most serious and devastating complications of diabetes and account for a significant decrease in quality of life and costly healthcare expenses worldwide. This condition affects around 15% of diabetic patients and is one of the leading causes of lower limb amputations. DFUs generally present poor clinical outcomes, mainly due to the impaired healing process and the elevated risk of microbial infections which leads to tissue damage. Nowadays, antimicrobial resistance poses a rising threat to global health, thus hampering DFU treatment and care. Faced with this reality, it is pivotal to find greener and less environmentally impactful alternatives for fighting these resistant microbes. Antimicrobial peptides are small molecules that play a crucial role in the innate immune system of the host and can be found in nature. Some of these molecules have shown broad-spectrum antimicrobial properties and wound-healing activity, making them good potential therapeutic compounds to treat DFUs. This review aims to describe antimicrobial peptides derived from green, eco-friendly processes that can be used as potential therapeutic compounds to treat DFUs, thereby granting a better quality of life to patients and their families while protecting our fundamental bio-resources.

Dysregulation of endoplasmic reticulum stress response in skin wounds in a streptozotocin-induced diabetes mouse model.

Dysfunction in key cellular organelles has been linked to diabetic complications. This study intended to investigate the alterations in the unfolded protein response (UPR), autophagy, and mitochondrial function, which are part of the endoplasmic reticulum (ER) stress response, in wound healing (WH) under diabetes conditions. WH mouse models were used to evaluate the UPR, autophagy, mitochondrial fusion, fission, and biogenesis as well as mitophagy in the skin of control and diabetic mice at baseline and 10 days after wounding. The autophagic flux in response to high-glucose conditions was also evaluated in keratinocyte and fibroblast cell cultures. WH was impaired in the diabetic mouse model, and we found that the UPR and autophagy pathways were activated in skin wounds of control mice and in the non-wounded skin of diabetic mice. Moreover, high-glucose conditions induced autophagy in the keratinocyte and fibroblast cell cultures. However, mitophagy did not change in the skin of diabetic mice or the wounded skin. In addition, mitochondrial fusion was activated in control but not in the skin wounds of diabetic mice, while mitochondrial biogenesis is downregulated in the skin of diabetic mice. In conclusion, the activation of the UPR, autophagy, and mitochondrial remodeling are crucial for a proper WH. These results suggest that the increase in ER stress and autophagy in the skin of diabetic mice at baseline significantly escalated to pathological levels after wounding, contributing to impaired WH in diabetes.

Circulating microRNA levels differ in the early stages of insulin resistance in prepubertal children with obesity.

AIMS: The increasing prevalence of childhood obesity escalates the risk for related complications. Circulating microRNAs (miRNAs) have been suggested as good predictive markers of insulin resistance in those with obesity. The aim was to identify a circulating miRNA profile that reflects insulin resistance in prepubertal children with obesity. MATERIAL AND METHODS: Plasma miRNAs were measured in prepubertal children (n = 63, 5-9 years) using TaqMan Advanced miRNA Human Serum/Plasma plates and then were validated by RT-qPCR. Subjects were divided into normal weight (n = 20, NW) and overweight or obese (n = 43, OW/OB) groups according to their BMI z-scores. The OW/OB group was further subdivided into insulin sensitive or metabolically healthy obese (n = 26, MHO) and insulin resistant or metabolically unhealthy obese (n = 17, MUO) according to HOMA-IR. KEY FINDINGS: While no differences were observed in the fasting plasma glucose levels, serum insulin levels were significantly elevated in the OW/OB compared to the NW group. Of 188 screened miRNAs, eleven were differentially expressed between the NW and OW/OB groups. Validation confirmed increased circulating levels of miR-146a-5p and miR-18a-5p in the OW/OB group, which correlated with BMI z-score. Interestingly, miR-146a-5p was also correlated with HOMA-IR index. While only miR-18a-5p was upregulated in the OW/OB children, independently of their degree of insulin sensitivity, miR-146-5p, miR-423-3p and miR-152-3p were associated with insulin resistance. SIGNIFICANCE: The present study provides evidence of molecular alterations that occur early in life in prepubertal obesity. These alterations may potentially be crucial for targeted prevention or prompt precision therapeutic development and subsequent interventions.

Effects of combined training during the COVID-19 pandemic on metabolic health and quality of life in sedentary workers: A randomized controlled study.

This study aimed to analyze the effects of a combined training (CT) program performed during the first national lockdown due to the COVID-19 pandemic on body composition, metabolic profile, quality of life and stress in sedentary workers, and examines whether changes in the metabolic profile are associated with changes in health-related outcomes which are modifiable by exercise. We evaluated 31 sedentary workers (48.26 ± 7.89 years old). Participants were randomly assigned to a CT group (i.e., performed 16 weeks of exercise) or to a non-exercise control group. The CT program consisted of 16-week of resistance and aerobic exercise. Body composition, glycemic and lipidic profiles, cardiorespiratory fitness (CRF), health-related quality of life and stress levels were assessed pre- and post-intervention. After the intervention period, the CT group demonstrated significantly lower waist and hip circumference (p < 0.05) values than the control group. The control group significantly increased the fasting glucose and HOMA-IR after 16 weeks follow-up (+4.74 mg/dL, p = 0.029; and +0.41 units, p = 0.010, respectively), whiles no significant changes were observed in the CT group in the same parameters (+3.33 mg/dL, p = 0.176; and +0.04 units, p = 0.628, respectively). No changes were observed in the lipid profile for either group (p > 0.05). A significant positive relationship was detected between the change in BMI with the changes in insulin and HOMA-IR (r = 0.643, p = 0.024; and r = 0.605, p = 0.037, respectively). In addition, the changes in CRF were negatively associated with the changes in total cholesterol (r = -0.578, p = 0.049). We observed differences between groups on perceived stress levels and physical, psychological, and environmental domains of quality of life, with the CT group showing better results. Moreover, the CT group improved perceived life satisfaction (+3.17 points, p = 0.038). The findings of the present study suggest that the participants who remained physically active during the first pandemic-related lockdown were able to mitigate the deleterious effects associated with a sedentary lifestyle.

Heme Oxygenase-1 as Therapeutic Target for Diabetic Foot Ulcers.

A diabetic foot ulcer (DFU) is one of the major complications of diabetes. Wound healing under diabetic conditions is often impaired. This is in part due to the excessive oxidative stress, prolonged inflammation, immune cell dysfunction, delayed re-epithelialization, and decreased angiogenesis present at the wound site. As a result of these multifactorial impaired healing pathways, it has been difficult to develop effective therapeutic strategies for DFU. Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in heme degradation generating carbon monoxide (CO), biliverdin (BV) which is converted into bilirubin (BR), and iron. HO-1 is a potent antioxidant. It can act as an anti-inflammatory, proliferative, angiogenic and cytoprotective enzyme. Due to its biological functions, HO-1 plays a very important role in wound healing, in part mediated through the biologically active end products generated by its enzymatic activity, particularly CO, BV, and BR. Therapeutic strategies involving the activation of HO-1, or the topical application of its biologically active end products are important in diabetic wound healing. Therefore, HO-1 is an attractive therapeutic target for DFU treatment. This review will provide an overview and discussion of the importance of HO-1 as a therapeutic target for diabetic wound healing.

Mitochondrial respiration in thoracic perivascular adipose tissue of diabetic mice.

Introduction: Thoracic perivascular adipose tissue (tPVAT) has a phenotype resembling brown AT. Dysfunctional tPVAT appears to be linked to vascular dysfunction. Methods: We evaluated uncoupling protein 1 (UCP1) expression by Western blot, oxidative stress by measuring lipid peroxidation, the antioxidant capacity by HPLC and spectrophotometry, and mitochondrial respiration by high-resolution respirometry (HRR) in tPVAT, compared to inguinal white AT (iWAT), obtained from non-diabetic (NDM) and streptozocin-induced diabetic (STZ-DM) mice. Mitochondrial respiration was assessed by HRR using protocol 1: complex I and II oxidative phosphorylation (OXPHOS) and protocol 2: fatty acid oxidation (FAO) OXPHOS. OXPHOS capacity in tPVAT was also evaluated after UCP1 inhibition by guanosine 5'-diphosphate (GDP). Results: UCP1 expression was higher in tPVAT when compared with iWAT in both NDM and STZ-DM mice. The malondialdehyde concentration was elevated in tPVAT from STZ-DM compared to NDM mice. Glutathione peroxidase and reductase activities, as well as reduced glutathione levels, were not different between tPVAT from NDM and STZ-DM mice but were lower compared to iWAT of STZ-DM mice. OXPHOS capacity of tPVAT was significantly decreased after UCP1 inhibition by GDP in protocol 1. While there were no differences in the OXPHOS capacity between NDM and STZ-DM mice in protocol 1, it was increased in STZ-DM compared to NDM mice in protocol 2. Moreover, complex II- and FAO-linked respiration were elevated in STZ-DM mice under UCP1 inhibition. Conclusions: Pharmacological therapies could be targeted to modulate UCP1 activity with a significant impact in the uncoupling of mitochondrial bioenergetics in tPVAT.

Effectiveness of Two Stress Reduction Interventions in Patients with Chronic Diabetic Foot Ulcers (PSY-DFU): Protocol for a Longitudinal RCT with a Nested Qualitative Study Involving Family Caregivers.

Diabetic foot ulcer (DFU) is the leading cause of lower-limb amputations, with a significant impact on patients, families, and society. Since DFU medical treatments represent a major socioeconomic burden, cost-effective interventions are needed. This trial aims to assess the effectiveness of a muscle relaxation intervention compared to a hypnosis intervention versus active and passive control groups on DFU healing, physiological indicators of healing prognosis, and quality of life (QoL) in clinically distressed patients with a chronic DFU. A multicenter, randomized controlled trial with three assessment moments (baseline, two months post-intervention, and four months follow-up) will be conducted. Approximately 170 patients will be randomized and allocated to either treatment or control groups. Primary outcomes will be DFU healing, physiological indicators of healing prognosis, and QoL. Secondary outcomes will include perceived stress, psychological morbidity, and DFU representations. The efficacy of sessions on DFU healing will be qualitatively assessed in 12 patients allocated to the treatment and active control groups, as well as their family caregivers. This study will provide evidence regarding the effectiveness of two psychological interventions for the DFU healing process and the QoL of patients, with direct clinical relevance regarding DFU treatment and recurrence.

Putative Biomarkers in Tears for Diabetic Retinopathy Diagnosis.

Purpose: Tear fluid biomarkers may offer a non-invasive strategy for detecting diabetic patients with increased risk of developing diabetic retinopathy (DR) or increased disease progression, thus helping both improving diagnostic accuracy and understanding the pathophysiology of the disease. Here, we assessed the tear fluid of nondiabetic individuals, diabetic patients with no DR, and diabetic patients with nonproliferative DR (NPDR) or with proliferative DR (PDR) to find putative biomarkers for the diagnosis and staging of DR. Methods: Tear fluid samples were collected using Schirmer test strips from a cohort with 12 controls and 54 Type 2 Diabetes (T2D) patients, and then analyzed using mass spectrometry (MS)-based shotgun proteomics and bead-based multiplex assay. Tear fluid-derived small extracellular vesicles (EVs) were analyzed by transmission electron microscopy, Western Blotting, and nano tracking. Results: Proteomics analysis revealed that among the 682 reliably quantified proteins in tear fluid, 42 and 26 were differentially expressed in NPDR and PDR, respectively, comparing to the control group. Data are available via ProteomeXchange with identifier PXD033101. By multicomparison analyses, we also found significant changes in 32 proteins. Gene ontology (GO) annotations showed that most of these proteins are associated with oxidative stress and small EVs. Indeed, we also found that tear fluid is particularly enriched in small EVs. T2D patients with NPDR have higher IL-2/-5/-18, TNF, MMP-2/-3/-9 concentrations than the controls. In the PDR group, IL-5/-18 and MMP-3/-9 concentrations were significantly higher, whereas IL-13 was lower, compared to the controls. Conclusions: Overall, the results show alterations in tear fluid proteins profile in diabetic patients with retinopathy. Promising candidate biomarkers identified need to be validated in a large sample cohort.

Effect of excess weight and insulin resistance on DNA methylation in prepubertal children.

Epigenetic mechanisms, such as DNA methylation, regulate gene expression and play a role in the development of insulin resistance. This study evaluates how the BMI z-score (BMIz) and the homeostatic model assessment of insulin resistance (HOMA-IR), alone or in combination, relate to clinical outcomes and DNA methylation patterns in prepubertal children. DNA methylation in peripheral blood mononuclear cells (PBMCs) and clinical outcomes were measured in a cohort of 41 prepubertal children. Children with higher HOMA-IR had higher blood pressure and plasma lactate levels while children with higher BMIz had higher triglycerides levels. Moreover, the DNA methylation analysis demonstrated that a 1 unit increase in the BMIz was associated with a 0.41 (95% CI: 0.29, 0.53) increase in methylation of a CpG near the PPP6R2 gene. This gene is important in the regulation of NF-kB expression. However, there was no strong evidence that the BMIz and the HOMA-IR were synergistically related to any clinical or DNA methylation outcomes. In summary, the results suggest that obesity and insulin resistance may impact metabolic health both independently in prepubertal children. In addition, obesity also has an impact on the DNA methylation of the PPP6R2 gene. This may be a novel underlying starting point for the systemic inflammation associated with obesity and insulin resistance, in this population.

The Role of Nutraceutical Containing Polyphenols in Diabetes Prevention.

Research in pharmacological therapy has led to the availability of many antidiabetic agents. New recommendations for precision medicine and particularly precision nutrition may greatly contribute to the control and especially to the prevention of diabetes. This scenario greatly encourages the search for novel non-pharmaceutical molecules. In line with this, the daily and long-term consumption of diets rich in phenolic compounds, together with a healthy lifestyle, may have a protective role against the development of type 2 diabetes. In the framework of the described studies, there is clear evidence that the bio accessibility, bioavailability, and the gut microbiota are indeed affected by: the way phenolic compounds are consumed (acutely or chronically; as pure compounds, extracts, or in-side a whole meal) and the amount and the type of phenolic compounds (ex-tractable or non-extractable/macromolecular antioxidants, including non-bioavailable polyphenols and plant matrix complexed structures). In this review, we report possible effects of important, commonly consumed, phenolic-based nutraceuticals in pre-clinical and clinical diabetes studies. We highlight their mechanisms of action and their potential effects in health promotion. Translation of this nutraceutical-based approach still requires more and larger clinical trials for better elucidation of the mechanism of action toward clinical applications.

Stress-Reducing Psychological Interventions as Adjuvant Therapies for Diabetic Chronic Wounds.

BACKGROUND: Diabetic foot ulcers (DFUs) are a major complication of diabetes mellitus and a leading cause of lower limb amputation. Interventions to reduce psychological stress may have the potential to improve self-care and greatly reduce the morbidity and mortality associated with DFU. This review is focused on the consequences of psychological stress in wound healing and reflects on the effects of currently used psychological stress-reducing interventions in patients with DFU, proposing new applications for currently used stress-reduction interventions. RESULTS: Stress is a natural and fundamental survival mechanism that becomes harmful when chronic. DFU is associated with high levels of anxiety and chronic psychological stress. Chronic stressinduced cortisol and adrenaline release impair wound healing, independently of the stressor. Psychological stress-reducing interventions, such as relaxation with guided imagery, biofeedback-assisted relaxation, mindfulness-based strategies, and hypnosis, can lead to a reduction in perceived stress and improve wound healing by reducing wound inflammation and pain while improving glycemic control. All stress reduction interventions also lead to pain relief and improved patient's quality of life. CONCLUSION: Psychological stress-reducing interventions are promising adjuvant therapies for DFU. Their clinical application can improve self-care by tackling patient's expectations, anxieties, and fears. They can also help patients manage stress and pain while reducing wound inflammation and improving wound healing.

Adipose-related microRNAs as modulators of the cardiovascular system: the role of epicardial adipose tissue.

Adipose tissue expansion and subsequent metabolic dysfunction has been considered one of the major risk factors for development of cardiometabolic disease. Epicardial adipose tissue (EAT) in particular is a unique subtype of visceral adipose tissue located on the surface of the heart, around the coronary arteries. Due to its proximity, EAT can modulate the local metabolic and immune function of cardiomyocytes and coronary arteries. Several microRNAs have been described as key players in both cardiac and vascular function that when dysregulated will contribute to dysfunction. Here we review the influence of obesity in the crosstalk between specific adipose tissue types, in particular the EAT-secreted microRNAs, as key modulators of cardiac disease progression, not only as early biomarkers but also as therapeutic targets for cardiometabolic disease.